The blood glucose level in the body is controlled by the balance between the hypoglycemic action of insulin and the blood glucose-increasing action of adrenalin, glucagon, glucocorticoid, etc. More specifically, insulin inhibits glycogenolysis and gluconeogenesis in the liver to suppress the production of glucose and reduce the amount of glucose released from the liver into the blood; and, at the same time, insulin increases glucose uptake into skeletal muscles and white adipose tissues, thereby lowering the blood glucose level. In contrast, adrenalin, glucagon, etc. promote glycogenolysis and gluconeogenesis in the liver and enhance glucose release therefrom, thereby increasing the blood glucose level.
Diabetes is a metabolic disease in which a hyperglycemic state persists due to an acute or chronical decrease in the action of insulin, resulting in disorders of sugar metabolism, lipid metabolism, amino acid metabolism, etc.
Diabetes is categorized as either insulin-dependent or non-insulin-dependent. To treat patients with insulin-dependent diabetes (type 1 diabetes mellitus), whose insulin secretory capacity is reduced or lost, dietary therapy and oral hypoglycemic agents are ineffective, and the administration of insulin is the only treatment. In contrast, to treat patients with non-insulin-dependent diabetes, who account for 90 percent of diabetic patients, although their insulin action is low compared with that of normal people, the administration of insulin is not always required, and alimentary therapy and exercise therapy are usually performed. When these therapies are not sufficient, chemotherapy by hypoglycemic agents is used concomitantly.
As described above, diabetes is a disease resulting in metabolic disorders due to a persistent hyperglycemic condition. Therefore, it is a troublesome disease that may be accompanied by many complications in the eyes, kidneys, nervous system, cardiovascular system, skin, etc. Such complications are generally considered to be decreased by controlling the blood glucose level to near normal levels (Non-Patent Literature (NPL) 1).
Known pharmaceutical preparations for ameliorating a hyperglycemic condition include insulin preparations, sulfonylurea preparations, biguanide preparations, insulin resistance improvers, α-glucosidase inhibitors, etc. Insulin preparations are therapeutic agents for insulin-dependent diabetes mellitus. Insulin preparations reliably lower blood glucose levels, but carry the risk of causing hypoglycemia. Sulfonylurea preparations are drugs that lower blood glucose levels by enhancing endogenous insulin secretion by stimulating pancreatic β-cells. Sulfonylurea preparations may cause hypoglycemia as a side effect due to the secretion of insulin that is induced irrespective of blood glucose levels. Biguanide preparations are drugs that lower blood glucose levels by inhibiting gluconeogenesis in the liver, increasing sugar consumption in the skeletal muscles etc., and inhibiting intestinal absorption of sugars. Biguanide preparations have the advantage of not causing hypoglycemia in either normal subjects or diabetic patients, but are likely to cause comparatively severe lactic acidosis. Insulin resistance improvers (e.g., thiazolidine derivatives etc.) are drugs that lower blood glucose levels by increasing the action of insulin and activating insulin receptor kinases. However, the following problems of insulin resistance improvers have been pointed out: digestive symptoms, edema, etc. develop as side effects; the amounts of red blood cells, hematocrit and hemoglobin are decreased; and the amount of LDH is increased (Non-Patent Literature (NPL) 2). α-Glucosidase inhibitors exhibit an effect of inhibiting an increase in after-meal blood glucose level by retarding the digestion and absorption of sugars in the gastrointestinal tract, but have problematic side effects such as a bloated sensation, borborygmus, and diarrhea (Non-Patent Literature (NPL) 3).
Thus, a decisive method for effectively treating or preventing diabetes and diabetic complications has yet to be established.
Recently, peptides that have an effect of inhibiting an increase in blood glucose level (i.e., an inhibitory effect on an increase in blood glucose level) and an effect of enhancing insulin secretion (an insulin secretion-enhancing effect) have been receiving attention. For example, Patent Literatures (PTLs) 1 to 3 suggest using such a peptide as an active ingredient of antidiabetics.